RIPK1/RIPK3信号通路介导的坏死性凋亡在ALI/ARDS发病中的作用及机制研究

Necroptosis is a newly discovered type of cell death. The latest researches have clarified necroptosis is regulated by RIPK1/RIPK3 signaling pathway and this signaling pathway can be specifically inhibited by Necrostatin-1 (Nec-1, the RIPK1 inhibitor). Existing studies show that: necroptosis is involved in the inflammatory response and the injury of tissues and cells in many diseases; necroptosis can induce uncontrolled inflammation by releasing DAMPs; the inhibition of necroptosis can improve prognosis of several diseases. However, there is no research about the role and the mechanism of necroptosis in the pathogenesis of acute lung injury (ALI). Accordingly, we intend to construct mouse ALI model and use Nec-1 to interfere in this model, and to detect the expression levels of active RIPK1/RIPK3 proteins and the expression levels of DAMPs. We plan to clarify whether necroptosis is involved in the pathogenesis of ALI and whether DAMPs are released during the process of necroptosis which can induce sustained inflammation in ALI. We also want to determine whether the inhibition of necroptosis can improve the prognosis of ALI. Furthermore, we attempt to combine our previous studies to examine whether Resolvin D1 attenuate mouse ALI through the inhibition of necroptosis and DAMPs releasing.

坏死性凋亡是近年来新发现的一种细胞死亡方式，最新研究阐明坏死性凋亡受RIPK1/RIPK3信号通路调节，并且被Necrostatin-1（Nec-1，RIPK1抑制剂)特异性抑制。现有研究显示：坏死性凋亡参与多种疾病的炎症反应及组织细胞损伤过程；坏死性凋亡过程释放损伤相关分子（DAMPs）诱导炎症反应失控；抑制坏死性凋亡可改善疾病预后。而坏死性凋亡在急性肺损伤（ALI）中的作用及机制尚无研究。故本课题拟构建小鼠ALI模型并利用Nec-1干预小鼠ALI模型，通过检测RIPK1/RIPK3信号蛋白活化水平、检测DAMPs表达水平，明确坏死性凋亡是否参与ALI发病过程；坏死性凋亡是否释放DAMPs持续诱导ALI炎症反应；抑制坏死性凋亡能否改善ALI预后。同时结合我们的前期研究，探讨消退素Resolvin D1减轻小鼠ALI是否与其抑制坏死性凋亡过程及DAMPs释放相关。